PROJECT SUMMARY Peripheral artery disease (PAD) is a serious cardiovascular disease affecting 200 million people worldwide. PAD is defined by a blockage of arteries in the lower extremities, and is associated with pain, poor wound healing, and without intervention, limb loss and death. Drug-coated balloons (DCB) are an emerging clinical intervention aimed at clearing blocked arteries, particularly those that are difficult to treat. PAD is a particular case for DCB utility. These arteries are poor candidates for stenting because of a high degree of stent fracture due to flexure and contraction of muscle. In fact, balloon angioplasty without stenting is the first line of therapy in PAD. By coating the balloon with a drug, it is possible to limit the re-narrowing of the artery that often occurs after angioplasty. All commercial DCB use a chemotherapy agent, paclitaxel, applied directly to the balloon surface, causing concern about its potential systemic toxicity upon non-specific release into the circulation. In fact, a recent report suggests that use of paclitaxel coated balloons in the lower limbs leads to an increased risk of death. Thus, alternatives to paclitaxel for DCB are critical. The PI has shown that two natural products, resveratrol and quercetin, synergize to significantly reduce vessel re-narrowing, while promoting vascular healing. Specifically, they reduce the adverse proliferation of vascular smooth muscle cells, but also reduce inflammation and platelet activation while promoting the re- growth of the protective endothelial layer. In prior studies, their use on a drug eluting stent showed dramatic efficacy in small animal models. However, the design of a DCB presents unique engineering challenges, in that the drug must be delivered to target lesions after only a brief balloon inflation. The team has developed an innovative delivery system that entraps the compounds and releases them slowly over time. The investigators propose a DCB in which drug-entrapped polymeric nanoparticles (pNPs) remain adhered to the surface of a balloon. Upon inflation within the artery, the positively charged pNP transfer to the negatively-charged phospholipid membrane comprising the artery wall. Since we use natural products with high safety profiles, our drugs should also exhibit less systemic toxicity if released systemically. To finalize development of our prototype, in this Phase I proposal we will optimize an electrospray process for achieving a high quality coating of our polyphenol:pNP delivery system onto an angioplasty balloon surface. The balloon coating will be evaluated for drug loading, uniformity and retention on the balloon surface. Once optimized, the DCB will be inflated in an artery of a rodent model to ensure that appreciable drug levels are achieved within the vessel for several days after angioplasty. The significance of this polyphenol-coated DCB is that by promoting vascular healing (re-endothelialization), its use in vascular interventions could reduce the need for anti-platelet therapies and repeat intervention. Moreover, the large safety profile of these polyphenols and our use of pNPs for their entrapment and controllable release should provide for less systemic toxicity and safer long-term outcomes.